Engaging Isatins and Amino Acids in Multicomponent One-Pot 1,3-Dipolar Cycloaddition Reactions—Easy Access to Structural Diversity

Multicomponent reactions (MCRs) have undoubtedly emerged as the most indispensable tool for organic chemists worldwide, finding extensive utility in the synthesis of intricate natural products, heterocyclic molecules with significant bioactivity, and pharmaceutical agents. The multicomponent one-pot 1,3-dipolar cycloaddition reactions, which were initially conceptualized by Rolf Huisgen in 1960, find extensive application in contemporary heterocyclic chemistry. In terms of green synthesis, the multicomponent 1,3-dipolar cycloaddition is highly favored owing to its numerous advantages, including high step- and atom-economies, remarkable product diversity, as well as excellent efficiency and diastereoselectivity. Among the numerous pieces of research, the most fascinating reaction involves the utilization of azomethine ylides generated from isatins and amino acids that can be captured by various dipolarophiles. This approach offers a highly efficient and convenient method for constructing spiro-pyrrolidine oxindole scaffolds, which are crucial building blocks in biologically active molecules. Consequently, this review delves deeper into the dipolarophiles utilized in the 1,3-dipolar cycloaddition of isatins and amino acids over the past six years.


Introduction
Multicomponent reactions (MCRs) are a captivating field of chemical synthesis that have captured the attention of researchers worldwide.MCRs involve the simultaneous engagement of three or more components, resulting in products that incorporate the elements of all starting materials in their frameworks in one pot [1][2][3][4].This distinctive characteristic renders MCRs an exceptionally powerful tool for generating novel molecular structures with unparalleled diversity.One of the most appealing characteristics of MCRs is their capacity to rapidly enhance molecular diversity.By combining multiple reactants in a single step, chemists can create complex molecules with ease and efficiency.This offers synthetically robust strategies for step-economic diversification, enabling scientists to explore a wide range of novel molecular frameworks [5][6][7][8][9][10].Despite substantial progress in MCR research, the concurrent formation of multiple chemical bonds and stereocenters in a single step continues to pose a daunting task for chemists.MCRs represent an exciting frontier in contemporary chemistry, which have immense potential for advancing our understanding of chemical synthesis and unlocking novel avenues for drug discovery and other applications.
Spiro-oxindole motifs are widely recognized as pivotal components in natural products and biologically active molecules.These unique structural features provide a remarkable level of conformational rigidity, often resulting in enhanced biological activity for various biomolecules.In fact, the spiro-oxindole fusion has been demonstrated to impart unique biological properties upon several indole alkaloids and related synthetic compounds.As illustrated in Figure 1, the spiro-oxindole scaffold serves as the core structure for natural products with complex structures such as horsfiline [36], elacomine [37], rhynchophylline [38], spirotryprostatin A [39], alstomutinine C [40], and MI-219 [41].Furthermore, the prevalence of spiro-oxindole motifs in nature highlights their significance as fundamental building blocks for drug discovery.Spiropyrrolidine oxindole moieties are not only naturally occurring, but they can also be found in a wide range of structures that exhibit impressive pharmacological activities, including antidiabetic, antiparasitic, anticancer, MDM2 inhibitor, and antibacterial properties (Figure 1) [42][43][44][45].Given their significant importance in the field of medicine and healthcare, it is unsurprising that these valuable structures have garnered considerable attention from researchers around the world [46][47][48][49][50].An innovative approach involves multicomponent 1,3-dipolar cycloadditions of azomethine ylides through the decarboxylative condensation of α-amino acids with isatins, which has emerged as a practical tool for creating new spiropyrrolidine oxindole moieties with even more potent therapeutic effects [51][52][53].Noticeably, natural amino acids are abundant and environmentally benign feedstocks for synthetic chemistry.At the same time, isatins possess a unique structure consisting of an indole ring fused with a ketone group, which endows them with remarkable chemical and biological properties [54][55][56][57][58][59][60][61].Hence, the utilization of both amino acids and isatins effectively facilitates the synthesis of a diverse and complex library of spiropyrrolidine oxindole compounds.
This concise yet informative minireview explores the fascinating realm of intermolecular one-pot three-component 1,3-dipolar cycloaddition reactions involving azomethine ylides derived from isatins and amino acids, in conjunction with a diverse array of unsaturated groups serving as dienophiles.This approach offers a multitude of advantages, including environmentally friendly synthesis, accessibility, cost-effectiveness, diversity, and sustainability.The review is succinctly organized based on the structural types of dipolarophiles, encompassing those with C=C double bonds within the linear chains, exocyclic C=C double bonds, endocyclic C=C double bonds, and C=N double bonds.(Figure 2).The review is mainly focused on sources in the literature published from 2017 to 2023.

The Dipolarophiles Containing C=C Double Bond Location within the Linear Carbon Chains
In 2022, a novel and structurally complex series of 3,3 -pyrrolidinyl-spirooxindoles derivatives 3-4 containing four contiguous and two quaternary stereogenic centers were synthesized via the additive-free 1,3-dipolar cycloaddition reaction of isatin-derived azomethine ylides with α-cyano-α, β-unsaturated compounds [62].The desired products were obtained in high yields (up to 92%) and excellent diastereoselectivities (up to >25:1 dr).The regioselectivity of this reaction was found to be influenced by the steric effects of substrates, resulting in either αor γ-regioselectivity (Scheme 1).The remarkable versatility of pipecolic acid as a substrate for this reaction is evident, as it consistently yields compound 5 regardless of variations in electron-withdrawing groups, such as ester, cyano, or tosyl (Ts) (22 examples).

The Dipolarophiles Containing C=C Double Bond Location within the Linear Carbon Chains
In 2022, a novel and structurally complex series of 3,3′-pyrrolidinyl-spirooxindoles derivatives 3-4 containing four contiguous and two quaternary stereogenic centers were synthesized via the additive-free 1,3-dipolar cycloaddition reaction of isatin-derived azomethine ylides with α-cyano-α, β-unsaturated compounds [62].The desired products were obtained in high yields (up to 92%) and excellent diastereoselectivities (up to >25:1 dr).The regioselectivity of this reaction was found to be influenced by the steric effects of substrates, resulting in either α-or γ-regioselectivity (Scheme 1).The remarkable versatility of pipecolic acid as a substrate for this reaction is evident, as it consistently yields compound 5 regardless of variations in electron-withdrawing groups, such as ester, cyano, or tosyl (Ts) (22 examples).Previous studies have reported the use of amino acids, benzylamine [63,64], and trifluoroethylamine [65][66][67] as reagents for generating azomethine ylides with isatins.However, there are limited reports on the utilization of stabilized azomethine ylides such as α-amino acid esters in three-component 1,3-dipolar cycloaddition reactions.In 2018, Lu et al. developed a Ag-catalyzed [3 + 2] cycloaddition reaction of azomethine ylides generated in situ from the condensation of substituted isatins 6 and primary α-amino acid esters 7 with chalcones 8 (Scheme 2).This facile and efficient method enabled the synthesis of spiroquaternary stereocenters fused in a single ring structure, resulting in products 9 containing four consecutive stereocenters.The reaction proceeded smoothly under mild conditions, affording moderate to high yields (50-95%) of the desired products.Moreover, the versatility of these products was demonstrated through a series of functional group transformations including reduction, oxidation, hydrolysis, and amidization.It is worth mentioning that this methodology can be successfully applied to a wide range of substrates (>100 examples) [68].
Previous studies have reported the use of amino acids, benzylamine [63,64], and trifluoroethylamine [65][66][67] as reagents for generating azomethine ylides with isatins.However, there are limited reports on the utilization of stabilized azomethine ylides such as α-amino acid esters in three-component 1,3-dipolar cycloaddition reactions.In 2018, Lu et al. developed a Ag-catalyzed [3 + 2] cycloaddition reaction of azomethine ylides generated in situ from the condensation of substituted isatins 6 and primary α-amino acid esters 7 with chalcones 8 (Scheme 2).This facile and efficient method enabled the synthesis of spiroquaternary stereocenters fused in a single ring structure, resulting in products 9 containing four consecutive stereocenters.The reaction proceeded smoothly under mild conditions, affording moderate to high yields (50-95%) of the desired products.Moreover, the versatility of these products was demonstrated through a series of functional group transformations including reduction, oxidation, hydrolysis, and amidization.It is worth mentioning that this methodology can be successfully applied to a wide range of substrates (>100 examples) [68].Scheme 2. Ag-catalyzed [3 + 2] cycloaddition of substituted isatins and primary α-amino acid esters with chalcones.
In 2021, Quiroga et al. achieved a one-pot sequential three-component synthesis of novel spiro[indoline-pyrrolidine] derivatives 13 using trans-1,2-dibenzoylethylene 12 as the dipolarophile (Scheme 3).The reactions proceeded via a 1,3-dipolar cycloaddition between azomethine ylides generated in situ from the condensation of isatins 10 with sarcosine ethyl ester 11 under reflux conditions.This protocol offered mild reaction conditions and operational simplicity, while providing high regioselectivity and stereoselectivity.The regio-and stereochemical outcomes of this cycloaddition reaction were determined through spectroscopic analysis.The geometries and electronic structures of the resulting compounds were further investigated using DFT quantum chemical calculations, aiming to establish a comprehensive understanding of the experimental results [69].In 2021, the Maniam group successfully demonstrated a microwave-assisted, onepot, three-component 1,3-dipolar cycloaddition of azomethine ylides derived from Lproline and isatin with various β-nitrostyrenes 16 (Scheme 4).The resulting nitro-sox compounds (17b, 17d and 17e) were found to significantly inhibit HEWL amyloid fibril Scheme 2. Ag-catalyzed [3 + 2] cycloaddition of substituted isatins and primary α-amino acid esters with chalcones.
In 2021, Quiroga et al. achieved a one-pot sequential three-component synthesis of novel spiro[indoline-pyrrolidine] derivatives 13 using trans-1,2-dibenzoylethylene 12 as the dipolarophile (Scheme 3).The reactions proceeded via a 1,3-dipolar cycloaddition between azomethine ylides generated in situ from the condensation of isatins 10 with sarcosine ethyl ester 11 under reflux conditions.This protocol offered mild reaction conditions and operational simplicity, while providing high regioselectivity and stereoselectivity.The regio-and stereochemical outcomes of this cycloaddition reaction were determined through spectroscopic analysis.The geometries and electronic structures of the resulting compounds were further investigated using DFT quantum chemical calculations, aiming to establish a comprehensive understanding of the experimental results [69].In 2021, Quiroga et al. achieved a one-pot sequential three-component synthesis of novel spiro[indoline-pyrrolidine] derivatives 13 using trans-1,2-dibenzoylethylene 12 as the dipolarophile (Scheme 3).The reactions proceeded via a 1,3-dipolar cycloaddition between azomethine ylides generated in situ from the condensation of isatins 10 with sarcosine ethyl ester 11 under reflux conditions.This protocol offered mild reaction conditions and operational simplicity, while providing high regioselectivity and stereoselectivity.The regio-and stereochemical outcomes of this cycloaddition reaction were determined through spectroscopic analysis.The geometries and electronic structures of the resulting compounds were further investigated using DFT quantum chemical calculations, aiming to establish a comprehensive understanding of the experimental results [69].In 2021, the Maniam group successfully demonstrated a microwave-assisted, onepot, three-component 1,3-dipolar cycloaddition of azomethine ylides derived from Lproline and isatin with various β-nitrostyrenes 16 (Scheme 4).The resulting nitro-sox compounds (17b, 17d and 17e) were found to significantly inhibit HEWL amyloid fibril Scheme 3. Three-component one-pot reaction using trans-1,2-dibenzoylethylene 12 as the dipolarophile.
In 2021, the Maniam group successfully demonstrated a microwave-assisted, one-pot, three-component 1,3-dipolar cycloaddition of azomethine ylides derived from L-proline and isatin with various β-nitrostyrenes 16 (Scheme 4).The resulting nitro-sox compounds (17b, 17d and 17e) were found to significantly inhibit HEWL amyloid fibril formation by up to 55.4%, as determined by ThT studies.After conducting further investigations, it was discovered that the potential activity of these promising candidates against amyloid misfolding, a phenomenon associated with Alzheimer's disease pathology, was supported by various methods such as MTT assay, Raman spectroscopy, TEM, and molecular docking [70].
In 2021, Barakat reported the condensation of substituted isatin derivatives with L-proline to generate azomethine ylides.These ylides subsequently underwent threecomponent 1,3-dipolar cycloaddition reactions with chalcones based on a thiochromene scaffold.This reaction produced a series of new spiro-heterocycles engrafted with spirooxindole/pyrrolidine/thiochromene scaffolds 31 in a fully controlled regio-and stereoselective manner (Scheme 7).Importantly, promising results as good candidates for further studies were obtained from anti-cancer assays.For the breast cancer MCF-7 cell lines, compound 31d exhibited an IC 50 value of 7.36 ± 0.37 µM, while it also demonstrated greater activity against the MDA-MB231 breast cancer cell line with an IC 50 value of 9.44 ± 0.32 µM.Compounds 31f demonstrated greater potency against PC3 (IC 50 = 8.7 ± 0.7 µM), whereas hybrid 31k was most active against cervical cancer HeLa (IC 50 = 8.4 ± 0.5 µM) [73].
Scheme 7. Synthesis of a series of spiro-oxindole pyrrolidine-grafted thiochromene scaffolds as potential anticancer agents.
In 2021, Zhu et al. accomplished the synthesis of a library of functionalized coumarin ring-grafted spiro or dispiro-oxindole heterocycles via a simple and efficient one-pot three-component 1,3-dipolar cycloaddition reaction involving diverse dipolarophiles and In 2021, Barakat reported the condensation of substituted isatin derivatives with Lproline to generate azomethine ylides.These ylides subsequently underwent threecomponent 1,3-dipolar cycloaddition reactions with chalcones based on a thiochromene scaffold.This reaction produced a series of new spiro-heterocycles engrafted with spirooxindole/pyrrolidine/thiochromene scaffolds 31 in a fully controlled regio-and stereoselective manner (Scheme 7).Importantly, promising results as good candidates for further studies were obtained from anti-cancer assays.For the breast cancer MCF-7 cell lines, compound 31d exhibited an IC50 value of 7.36 ± 0.37 µM, while it also demonstrated greater activity against the MDA-MB231 breast cancer cell line with an IC50 value of 9.44 ± 0.32 µM.Compounds 31f demonstrated greater potency against PC3 (IC50 = 8.7 ± 0.7 µM), whereas hybrid 31k was most active against cervical cancer HeLa (IC50 = 8.4 ± 0.5 µM) [73].In 2021, Zhu et al. accomplished the synthesis of a library of functionalized coumarin ring-grafted spiro or dispiro-oxindole heterocycles via a simple and efficient one-pot three-component 1,3-dipolar cycloaddition reaction involving diverse dipolarophiles and azomethine ylides.This method resulted in the high-efficiency production of a wide range of coumarin-substituted spiro-oxindole and dispiro-oxindole derivatives containing pyrrolizidine/pyrrolothiazole/pyrrolidine moieties (34, 35, 37, 38) with high efficiency (Scheme 8).This approach offers several valuable features, notably including high product yields (up to 88%), a broad substrate scope (44 examples), mild reaction conditions, and a straightforward procedure.These characteristics make it an attractive and useful process for synthesizing biologically important compounds [74].
azomethine ylides.This method resulted in the high-efficiency production of a wide range of coumarin-substituted spiro-oxindole and dispiro-oxindole derivatives containing pyrrolizidine/pyrrolothiazole/pyrrolidine moieties (34, 35, 37, 38) with high efficiency (Scheme 8).This approach offers several valuable features, notably including high product yields (up to 88%), a broad substrate scope (44 examples), mild reaction conditions, and a straightforward procedure.These characteristics make it an attractive and useful process for synthesizing biologically important compounds [74].Piperine (trans-trans-isomer of 1-piperoyl piperidine), a novel family of alkamides derived from the medicinal plant Piper nigrum (family Piperaceae), has been recognized for its plethora of therapeutic biological activities including anti-inflammatory, antiarthritic, anti-nociceptive, anti-depression, anti-hypertension, anti-cancer, and antioxidant properties [75-77].In 2019, Hazra and colleagues further investigated the potential of isatin-based 1,3-dipolar cycloaddition by selecting piperine as their compound of choice.They successfully synthesized spiro-oxindole pyrrolizidine adducts through an intermolecular 1,3-dipolar azomethine ylide cycloaddition reaction in a multicomponent (MCR) atom-economical manner.Both double bonds in piperine undergo conjugation and generate two racemic regioisomeric adducts, 41 and 42, with a higher yield of the former (Scheme 9).The structures of these products were determined by utilizing a combination of 1D/2D NMR, mass spectral analysis, and X-ray crystallography for selected compounds.Additionally, chiral HPLC separation was employed to determine the specific rotation and CD spectra of the enantiomers for two racemic compounds [78].Piperine (trans-trans-isomer of 1-piperoyl piperidine), a novel family of alkamides derived from the medicinal plant Piper nigrum (family Piperaceae), has been recognized for its plethora of therapeutic biological activities including anti-inflammatory, antiarthritic, anti-nociceptive, anti-depression, anti-hypertension, anti-cancer, and antioxidant properties [75-77].In 2019, Hazra and colleagues further investigated the potential of isatinbased 1,3-dipolar cycloaddition by selecting piperine as their compound of choice.They successfully synthesized spiro-oxindole pyrrolizidine adducts through an intermolecular 1,3-dipolar azomethine ylide cycloaddition reaction in a multicomponent (MCR) atomeconomical manner.Both double bonds in piperine undergo conjugation and generate two racemic regioisomeric adducts, 41 and 42, with a higher yield of the former (Scheme 9).The structures of these products were determined by utilizing a combination of 1D/2D NMR, mass spectral analysis, and X-ray crystallography for selected compounds.Additionally, chiral HPLC separation was employed to determine the specific rotation and CD spectra of the enantiomers for two racemic compounds [78].
pyrrolizidine/pyrrolothiazole/pyrrolidine moieties (34, 35, 37, 38) with high efficiency (Scheme 8).This approach offers several valuable features, notably including high product yields (up to 88%), a broad substrate scope (44 examples), mild reaction conditions, and a straightforward procedure.These characteristics make it an attractive and useful process for synthesizing biologically important compounds [74].Piperine (trans-trans-isomer of 1-piperoyl piperidine), a novel family of alkamides derived from the medicinal plant Piper nigrum (family Piperaceae), has been recognized for its plethora of therapeutic biological activities including anti-inflammatory, antiarthritic, anti-nociceptive, anti-depression, anti-hypertension, anti-cancer, and antioxidant properties [75-77].In 2019, Hazra and colleagues further investigated the potential of isatin-based 1,3-dipolar cycloaddition by selecting piperine as their compound of choice.They successfully synthesized spiro-oxindole pyrrolizidine adducts through an intermolecular 1,3-dipolar azomethine ylide cycloaddition reaction in a multicomponent (MCR) atom-economical manner.Both double bonds in piperine undergo conjugation and generate two racemic regioisomeric adducts, 41 and 42, with a higher yield of the former (Scheme 9).The structures of these products were determined by utilizing a combination of 1D/2D NMR, mass spectral analysis, and X-ray crystallography for selected compounds.Additionally, chiral HPLC separation was employed to determine the specific rotation and CD spectra of the enantiomers for two racemic compounds [78].

Dipolarophiles Containing Exocyclic Unsaturated C=C Double Bonds
In 2020, Boudriga developed an efficient and practical strategy for the multicomponent 1,3-dipolar cycloaddition of (E)-3-benzylidene-1-phenyl-succinimides 45, isatin 43, and diverse α-amino acids 44.Under optimal conditions (MeOH/H 2 O, 6 h), succinimidesubstituted dispiropyrrolidine derivatives 46 were obtained with high regio-and diastereoselectivities (Scheme 10).The stereochemistry of these N-heterocycles has been confirmed by four X-ray diffraction studies.According to the proposed mechanism, the formation of the exo-regioisomer 46 via path A is more favorable because of the presence of a secondary orbital interaction (SOI), which occurs between the oxygen atom of the carbonyl of the diketone and the carbon atom of the carbonyl of the dipolarophile, as shown in Scheme 10.Conversely, the formation of the other regioisomers 46 is less favorable because of steric or electronic repulsion in their corresponding transition states.

Dipolarophiles Containing Exocyclic Unsaturated C=C Double Bonds
In 2020, Boudriga developed an efficient and practical strategy for the multicomponent 1,3-dipolar cycloaddition of (E)-3-benzylidene-1-phenyl-succinimides 45, isatin 43, and diverse α-amino acids 44.Under optimal conditions (MeOH/H2O, 6 h), succinimide-substituted dispiropyrrolidine derivatives 46 were obtained with high regioand diastereoselectivities (Scheme 10).The stereochemistry of these N-heterocycles has been confirmed by four X-ray diffraction studies.According to the proposed mechanism, the formation of the exo-regioisomer 46 via path A is more favorable because of the presence of a secondary orbital interaction (SOI), which occurs between the oxygen atom of the carbonyl of the diketone and the carbon atom of the carbonyl of the dipolarophile, as shown in Scheme 10.Conversely, the formation of the other regioisomers 46′ is less favorable because of steric or electronic repulsion in their corresponding transition states.Scheme 10.Three-component access to functionalized spiropyrrolidine heterocyclic scaffolds and their cholinesterase inhibitory activity.
In addition, several synthesized compounds exhibit greater inhibition of acetylcholinesterase (AChE) than butyrylcholinesterase (BChE).Among the 17 tested compounds, 5 compounds demonstrate significant AChE inhibition with IC50 values ranging from 11.42 to 22.21 µM.Compound 46n, which possesses the most potent AChE inhibitory activity (IC50 = 11.42 ± 0.45 µM), was subjected to a molecular docking study that revealed its binding to the peripheral anionic site of AChE enzymes (Scheme 10) [79].
In 2022, El-Tahawy et al. reported the synthesis of a novel series of spiropyrrolizidine derivatives through a three-component 1,3-dipolar cycloaddition reaction involving (E)-3-arylidene-1-methyl-pyrrolidine-2,5-diones 49, L-proline, and cyclic ketones isatins.Notably, the authors observed that both regioselectivity and stereoselectivity were strongly influenced by solvent properties and reaction time (Scheme 11).Under optimal conditions (MeOH at 80 °C for 12 h), besides the anticipated cycloaddition product 50, its corresponding regioisomer 51 and diastereoisomer 52 were also synthesized.For the observed epimerization, the authors proposed a ring-opening retro-Mannich reaction for compound 52, which possesses an unusual relative stereochemistry.Regioisomer 51 Scheme 10.Three-component access to functionalized spiropyrrolidine heterocyclic scaffolds and their cholinesterase inhibitory activity.
In addition, several synthesized compounds exhibit greater inhibition of acetylcholinesterase (AChE) than butyrylcholinesterase (BChE).Among the 17 tested compounds, 5 compounds demonstrate significant AChE inhibition with IC 50 values ranging from 11.42 to 22.21 µM.Compound 46n, which possesses the most potent AChE inhibitory activity (IC 50 = 11.42 ± 0.45 µM), was subjected to a molecular docking study that revealed its binding to the peripheral anionic site of AChE enzymes (Scheme 10) [79].
In 2022, El-Tahawy et al. reported the synthesis of a novel series of spiropyrrolizidine derivatives through a three-component 1,3-dipolar cycloaddition reaction involving (E)-3-arylidene-1-methyl-pyrrolidine-2,5-diones 49, L-proline, and cyclic ketones isatins.Notably, the authors observed that both regioselectivity and stereoselectivity were strongly influenced by solvent properties and reaction time (Scheme 11).Under optimal conditions (MeOH at 80 • C for 12 h), besides the anticipated cycloaddition product 50, its corresponding regioisomer 51 and diastereoisomer 52 were also synthesized.For the observed epimerization, the authors proposed a ring-opening retro-Mannich reaction for compound 52, which possesses an unusual relative stereochemistry.Regioisomer 51 formed via cycloadduct 50 could also undergo a slow 1,3-dipolar retro-cycloadduct to generate W-conformal azomethine ylides D whose cycloadduct with dipolarophile 49 would lead to the formation of unexpected regioisomers 51.The proposed mechanism and resulting yields are rationalized by theoretical calculations, and the relatively high yield observed for the formation of 50 is related to the stability of its transition state when compared with the other isomers.Furthermore, synthesized compounds underwent biological activity assays against a variety of microbial strains, revealing moderate to excellent antibacterial, antifungal, and anticoagulant activities [80].
generate W-conformal azomethine ylides D whose cycloadduct with dipolarophile 49 would lead to the formation of unexpected regioisomers 51.The proposed mechanism and resulting yields are rationalized by theoretical calculations, and the relatively high yield observed for the formation of 50 is related to the stability of its transition state when compared with the other isomers.Furthermore, synthesized compounds underwent biological activity assays against a variety of microbial strains, revealing moderate to excellent antibacterial, antifungal, and anticoagulant activities [80].Bis-spiro-oxindoles display a broad spectrum of biological activities, encompassing anticancer, antiviral, antibacterial, and anti-inflammatory effects [81,82].These compounds feature two spirocyclic rings fused together, rendering them an intriguing class of organic molecules.Their distinctive structural characteristics combined with their diverse bioactivities render them an appealing synthetic target.In 2019, Shankaraiah developed a diastereoselective and environmentally friendly one-pot protocol for synthesizing pyrrolidine-fused bis-spiro-oxindole 56 using 3-alkenyl oxindoles 55 as substrates (Scheme 12).The reactions were conducted under microwave conditions with ethanol as the solvent, without any additives or catalysts.This method exhibits broad substrate scope (19 examples), high atom economy, and is eco-friendly with excellent yields (up to 95%) [83].
In 2022, Maniam et al. disclosed a rapid microwave-assisted synthesis of novel pyrrolizidine bis-spiro-oxindoles compounds 60a-60c with high stereo-and regiospecificity, eliminating the need for extensive purification procedures (Scheme 13) [84].Significantly, initial screening of these compounds demonstrated promising activity against amyloid misfolding by actively interacting with highly amyloidogenic regions within the peptide.The advantageous characteristics of this one-pot three-component reaction include facile synthesis and potential anti-amyloidogenic properties.Bis-spiro-oxindoles display a broad spectrum of biological activities, encompassing anticancer, antiviral, antibacterial, and anti-inflammatory effects [81,82].These compounds feature two spirocyclic rings fused together, rendering them an intriguing class of organic molecules.Their distinctive structural characteristics combined with their diverse bioactivities render them an appealing synthetic target.In 2019, Shankaraiah developed a diastereoselective and environmentally friendly one-pot protocol for synthesizing pyrrolidine-fused bis-spiro-oxindole 56 using 3-alkenyl oxindoles 55 as substrates (Scheme 12).The reactions were conducted under microwave conditions with ethanol as the solvent, without any additives or catalysts.This method exhibits broad substrate scope (19 examples), high atom economy, and is eco-friendly with excellent yields (up to 95%) [83].
In 2022, Maniam et al. disclosed a rapid microwave-assisted synthesis of novel pyrrolizidine bis-spiro-oxindoles compounds 60a-60c with high stereo-and regiospecificity, eliminating the need for extensive purification procedures (Scheme 13) [84].Significantly, initial screening of these compounds demonstrated promising activity against amyloid misfolding by actively interacting with highly amyloidogenic regions within the peptide.The advantageous characteristics of this one-pot three-component reaction include facile synthesis and potential anti-amyloidogenic properties.
Similarly, with MeOH as the solvent and at a temperature of 30 • C, methyleneindolinones 63 could react with isatins and various primary amino acids in the three-component 1,3-dipolar cycloaddition reaction (Scheme 14).Pyrrolidinyl-dispirooxindole scaffolds 64 were easily obtained in excellent yields (34 examples and up to 99% yield), exhibiting a wide range of structural diversity and complexity.All amino acid types could smoothly participate in the reaction, with aliphatic amino acids typically yielding excellent results.However, chemical yields were reduced when functional groups such as hydroxyl or imidazole were attached, while diastereoselectivity was maintained.Additionally, this protocol was also applicable to N-substituted analogues of amino acids and exhibits comparable reactivities [85].
Similarly, with MeOH as the solvent and at a temperature of 30 °C, methyleneindolinones 63 could react with isatins and various primary amino acids in the three-component 1,3-dipolar cycloaddition reaction (Scheme 14).Pyrrolidinyl-dispirooxindole scaffolds 64 were easily obtained in excellent yields (34 examples and up to 99% yield), exhibiting a wide range of structural diversity and complexity.All amino acid types could smoothly participate in the reaction, with aliphatic amino acids typically yielding excellent results.However, chemical yields were reduced when functional groups such as hydroxyl or imidazole were attached, while diastereoselectivity was Similarly, with MeOH as the solvent and at a temperature of 30 °C, methyleneindolinones 63 could react with isatins and various primary amino acids in the three-component 1,3-dipolar cycloaddition reaction (Scheme 14).Pyrrolidinyl-dispirooxindole scaffolds 64 were easily obtained in excellent yields (34 examples and up to 99% yield), exhibiting a wide range of structural diversity and complexity.All amino acid types could smoothly participate in the reaction, with aliphatic amino acids typically yielding excellent results.However, chemical yields were reduced when functional groups such as hydroxyl or imidazole were attached, while diastereoselectivity was Scheme 13.Regioselective synthesis of pyrrolizidine bis-spiro-oxindoles as efficient antiamyloidogenic agents.
In 2020, with (E)-2-oxoindolin-3-ylidene acetyl sultam as reaction partner, Jadidi reported the synthesis of a highly enantioenriched bis-spiro-oxindole pyrrolizidine scaffold using 1,3-dipolar cycloaddition of isatin-derived azomethine ylides (Scheme 15).In addition, highly enantioenriched bis-spiro-oxindole pyrrolidines were generated in high yields and with high regio-and -diastereoselectivities (up to 99:1) by utilizing this chiral auxiliary controlled method.It should be noted that these products were completely stable in a solid state.However, when the pure samples were kept as a solution in room temperature, the other diastereomers 68 were gradually observed after about 2 h.The author specu-lated that these obtained cycloadducts underwent retro-Mannich ring-opening cyclization and produced new diastereoisomers of the bis-spiro-oxindole pyrrolizidine/pyrrolidines skeleton, which could not be accessed by direct 1,3-dipolar cycloaddition [86].
Molecules 2023, 28, x FOR PEER REVIEW 12 of 26 maintained.Additionally, this protocol was also applicable to N-substituted analogues of amino acids and exhibits comparable reactivities [85].
In 2020, with (E)-2-oxoindolin-3-ylidene acetyl sultam as reaction partner, Jadidi reported the synthesis of a highly enantioenriched bis-spiro-oxindole pyrrolizidine scaffold using 1,3-dipolar cycloaddition of isatin-derived azomethine ylides (Scheme 15).In addition, highly enantioenriched bis-spiro-oxindole pyrrolidines were generated in high yields and with high regio-and -diastereoselectivities (up to 99:1) by utilizing this chiral auxiliary controlled method.It should be noted that these products were completely stable in a solid state.However, when the pure samples were kept as a solution in room temperature, the other diastereomers 68′ were gradually observed after about 2 h.The author speculated that these obtained cycloadducts underwent retro-Mannich ringopening cyclization and produced new diastereoisomers of the bis-spiro-oxindole pyrrolizidine/pyrrolidines skeleton, which could not be accessed by direct 1,3-dipolar cycloaddition [86].In 2020, with (E)-2-oxoindolin-3-ylidene acetyl sultam as reaction partner, Jadidi reported the synthesis of a highly enantioenriched bis-spiro-oxindole pyrrolizidine scaffold using 1,3-dipolar cycloaddition of isatin-derived azomethine ylides (Scheme 15).In addition, highly enantioenriched bis-spiro-oxindole pyrrolidines were generated in high yields and with high regio-and -diastereoselectivities (up to 99:1) by utilizing this chiral auxiliary controlled method.It should be noted that these products were completely stable in a solid state.However, when the pure samples were kept as a solution in room temperature, the other diastereomers 68′ were gradually observed after about 2 h.The author speculated that these obtained cycloadducts underwent retro-Mannich ringopening cyclization and produced new diastereoisomers of the bis-spiro-oxindole pyrrolizidine/pyrrolidines skeleton, which could not be accessed by direct 1,3-dipolar cycloaddition [86].Developing effective strategies for single-step editing of the core skeleton of structurally complex compounds is a highly desirable yet challenging task.Dehydrocostus lactone and parthenolide are heterocyclic natural products of significant importance, as their biological activity may be influenced by their stereochemistry and substituents [88][89][90][91].In 2023, Liu et al. accomplished the synthesis of a structurally intriguing dehydrocostuslactone-inspired hybrid 79 via a 1,3-dipolar cycloaddition of isatin 75, proline and optically pure dehydrocostus lactone 77.Subsequently, in the presence of m-CPBA, they made an unexpected discovery that enabled bispiro[oxindole-oxazinane] skeletal editing of a pyrrolidine skeleton to a 1,2-oxazinane skeleton based on formal oxygen atom insertion into a carbon-nitrogen bond (Scheme 17).These structurally diverse and medicinally important compounds, which contain up to six adjacent stereocenters including two quaternary spirostereocenters, were synthesized in just two steps with excellent yields (up to 79% yield and >20:1 dr).Similarly, the synthesis of bispiro[oxindole-oxazinane] hybrids 82 inspired by parthenolide could be achieved using the same method.Developing effective strategies for single-step editing of the core skeleton of structurally complex compounds is a highly desirable yet challenging task.Dehydrocostus lactone and parthenolide are heterocyclic natural products of significant importance, as their biological activity may be influenced by their stereochemistry and substituents [88][89][90][91].In 2023, Liu et al. accomplished the synthesis of a structurally intriguing dehydrocostus-lactone-inspired hybrid 79 via a 1,3-dipolar cycloaddition of isatin 75, proline and optically pure dehydrocostus lactone 77.Subsequently, in the presence of m-CPBA, they made an unexpected discovery that enabled bispiro[oxindoleoxazinane] skeletal editing of a pyrrolidine skeleton to a 1,2-oxazinane skeleton based on formal oxygen insertion into a carbon-nitrogen bond (Scheme 17).These structurally diverse and medicinally compounds, which contain up to six adjacent stereocenters including two quaternary spiro-stereocenters, were synthesized in just two steps with excellent yields (up to 79% yield and >20:1 dr).Similarly, the synthesis of bispiro[oxindole-oxazinane] hybrids 82 inspired by parthenolide could be achieved using the same method.
The authors also provided the proposed mechanism (Scheme 17).First, the reaction of isatin 75a and proline led to azomethine ylide E via a dehydration/decarboxylation process, which could be added optically pure dehydrocostus lactone 77 in a to give cycloaddition compound 79a.Subsequently, N-oxidation with m-CPBA would lead to the formation of pyrrolidine-derived N-oxide skeleton 81a′.However, 81a′ was unstable, perhaps due to the unfavorable repulsion between three adjacent tetrasubstituted stereocenters, leading, subsequently, to the oxygen atom in the N-oxide group attacking the C3 spiro center of oxindole via a 1,2-migration process followed by a ring expansion to access the unexpected 1,2-oxazinane skeleton 81a.This protocol represents Scheme 16. [3 + 2] cycloaddition of azomethine ylides with a thiazolo[3,2-a]indole derivative.
Molecules 2023, 28, x FOR PEER REVIEW 14 of 26 a significant advancement in skeletal editing, as it is the first example of converting a pyrrolidine skeleton to a 1,2-oxazinane skeleton, thereby expanding the diversity of spirooxindoles [92].
Scheme 17. Synthesis of dehydrocostus-lactone-inspired hybrid and parthenolide-inspired hybrid via formal oxygen atom insertion.

Dipolarophiles Containing Endocyclic Unsaturated C=C Double Bonds
Based on our extensive interest in maleimide chemistry [93,94], our research group has successfully developed an efficient one-pot, three-component [3 + 2] cycloaddition reaction of azomethine ylides derived from α-dicarbonyl compounds (isatins, diketones, or keto esters) and amino acids with maleimides under mild conditions (Scheme 18).The cascade protocol demonstrates high efficiency and remarkable tolerance towards functional groups (28 examples), resulting in the formation of widely distributed Scheme 17. Synthesis of dehydrocostus-lactone-inspired hybrid and parthenolide-inspired hybrid via formal oxygen atom insertion.
The authors also provided the proposed mechanism (Scheme 17).First, the reaction of isatin 75a and proline led to azomethine ylide E via a dehydration/decarboxylation process, which could be added to optically pure dehydrocostus lactone 77 in a sequential manner to give cycloaddition compound 79a.Subsequently, N-oxidation with m-CPBA would lead to the formation of pyrrolidine-derived N-oxide skeleton 81a .However, 81a was unstable, perhaps due to the unfavorable repulsion between three adjacent tetrasubstituted stereocenters, leading, subsequently, to the oxygen atom in the N-oxide group attacking the C3 spiro center of oxindole via a 1,2-migration process followed by a ring expansion to access the unexpected 1,2-oxazinane skeleton 81a.This protocol represents a significant advancement in skeletal editing, as it is the first example of converting a pyrrolidine skeleton to a 1,2-oxazinane skeleton, thereby expanding the diversity of spiro-oxindoles [92].
involvement of strained oxabicyclic alkenes remains limited.Parthasarathy and coworkers explored 1,3-dipolar cycloaddition of azomethine ylides with heterobicyclic alkenes 89 at 80 °C for 6 h (Scheme 19a), and various fused spiropyrrolidine oxindoles were isolated in good yield [105].Our group noticed that the amino acids substrate scope was limited in sarcosine and proline.Subsequently, our research group investigated an environmentally friendly microwave-assisted multicomponent reaction involving isatins, α-amino acids (primary and secondary), and 1,4-dihydro-1,4-epoxynaphthalene (Scheme 19b).This reaction resulted in the formation of oxygen-bridged spiro-oxindoles 94 with high yields ranging from good to excellent (up to 94%) within a remarkably short time of only 15 min [106].Azomethine ylides generated in situ from isatins and sarcosine with 3-nitro-2-(trifluoromethyl)-2H-chromenes 95 in i-PrOH at 55-60 • C lead to the kinetically controlled products exo-spiro[chromeno [3,4-c]pyrrolidine-3,30-oxindoles] 97.When this reaction is carried out in 1,4-dioxane under reflux, the thermodynamically controlled endospiro[chromeno [3,4-c]pyrrolidine-1,30-oxindoles] 96 are preferably formed (Scheme 20).From a mechanistic perspective, due to the high electrophilicity of the double bond, several [3 + 2] cycloaddition reactions of 1,3-dipoles to nitroalkenes proceed via a nonconcerted Michael addition/Mannich reaction sequence.The introduction of the azomethine ylide to chromene 95 results in the formation of zwitterionic intermediates G, which subsequently undergo cyclization under thermodynamically controlled conditions to yield the corresponding products 96.However, it should be noted that this reaction is reversible and may result in the regeneration of the starting material.In contrast, under kinetic control, the dipole attacks the C-4 atom of chromene 95 via the less substituted C-1 atom, while under thermodynamic control, addition of ylide to chromene through the C-3 atom is more favorable.In addition to the kinetic control product 97, the zwitterionic intermediate H can be transformed into intermediate I by rotation around the C (3)-N bond, yielding another diastereomer 97 .Moreover, the study also investigated the cytotoxicity of certain spiro[chromeno- [3,4-c]pyrrolidine-oxindoles] substituted with CF 3 against the HeLa cell line using the MTT assay [107].
The heterocycle-based chromanone structures are considered privileged skeletons for their diverse biological activities in natural products [108][109][110].In 2019, Liu et al. developed a novel approach for the facile one-pot multicomponent synthesis of heterocyclefused spiro compounds 100, which integrated two potential pharmacophores, chromanone and pyrrolidinyl spiro-oxindoles, into a single molecule (Scheme 21).In contrast, the absence of the carboxylic acid group rendered 98 incapables of generating the desired cycloaddition product 100.A wide variety of products with three contiguous stereocenters were smoothly prepared with high efficiency (up to 87% yield and 20:1 dr).The compound obtained exhibited biological activities against human prostate cancer cells PC-3 and human leukemia cells K562; notably, the compound 100m exhibited IC 50 values of 21.10 µM and 33.72 µM for the two tested targets, respectively [111].
kinetic control, the dipole attacks the C-4 atom of chromene 95 via the less substituted C-1 atom, while under thermodynamic control, addition of ylide to chromene through the C-3 atom is more favorable.In addition to the kinetic control product 97, the zwitterionic intermediate H can be transformed into intermediate I by rotation around the C (3)-N bond, yielding another diastereomer 97′.Moreover, the study also investigated the cytotoxicity of certain spiro[chromeno- [3,4-c]pyrrolidine-oxindoles] substituted with CF3 against the HeLa cell line using the MTT assay [107].The heterocycle-based chromanone structures are considered privileged skeletons for their diverse biological activities in natural products [108][109][110].In 2019, Liu et al. developed a novel approach for the facile one-pot multicomponent synthesis of heterocycle-fused spiro compounds 100, which integrated two potential pharmacophores, chromanone and pyrrolidinyl spiro-oxindoles, into a single molecule (Scheme 21).In contrast, the absence of the carboxylic acid group rendered 98 incapables of generating the desired cycloaddition product 100.A wide variety of products with three contiguous stereocenters were smoothly prepared with high efficiency (up to 87% yield and 20:1 dr).The compound obtained exhibited biological activities against human prostate cancer cells PC-3 and human leukemia cells K562; notably, the compound 100m exhibited IC50 values of 21.10 µM and 33.72 µM for the two tested targets, respectively [111].
Cyclopropenes are fascinating molecules that have captured the attention of chemists for decades [112][113][114].The smallest possible unsaturated carbocycle, with their characteristic triangular shape, owes an incredible reactivity to 54.1 kcal/mol of strain energy.Releasing the strain energy enables cyclopropenes to undergo various reactions such as cycloadditions and hydrofunctionalizations [115][116][117][118].In 2017, Stepakov and coworkers disclosed a one-pot three-component reactions utilizing substituted isatins, αamino acids, and cyclopropenes 103 (Scheme 22).It is noteworthy that both dipeptide Gly-Gly and benzylamine can serve as the amine component for azomethine ylide generation.The in vitro anticancer activity of some of the obtained compounds against human leukemia K562 cell line was assessed using flow cytometry [119].Cyclopropenes are fascinating molecules that have captured the attention of chemists for decades [112][113][114].The smallest possible unsaturated carbocycle, with their characteristic triangular shape, owes an incredible reactivity to 54.1 kcal/mol of strain energy.
Releasing the strain energy enables cyclopropenes to undergo various reactions such as cycloadditions and hydrofunctionalizations [115][116][117][118].In 2017, Stepakov and co-workers disclosed a one-pot three-component reactions utilizing substituted isatins, α-amino acids, and cyclopropenes 103 (Scheme 22).It is noteworthy that both dipeptide Gly-Gly and benzylamine can serve as the amine component for azomethine ylide generation.The in vitro anticancer activity of some of the obtained compounds against human leukemia K562 cell line was assessed using flow cytometry [119].

Dipolarophiles Containing Unsaturated C=N Double Bonds
In terms of dipolarophiles of 1,3-dipolar cycloaddition, a considerable number of alkenes and alkynes have been subjected to 1,3-DC leading to the formation of various spiro-oxindolopyrrolidines and spiro-pyrrolines.On the other hand, the synthesis of analogous spiro-oxindoloimidazolidines using imines as dipolarophiles remains largely unexplored.Yang and co-workers developed a diversity-driven three-component 1,3dipolar cycloaddition of isatins, amino acids, and isatin-derived ketimines 107 (Scheme 23).A variety of dispiro-oxindole-imidazolidine frameworks featuring adjacent quaternary carbon centers were facilely obtained in excellent yields under mild conditions (at room temperature).This protocol can be readily scaled up with simplified purification steps without compromising the chemical outcome.The broad substrate scope (34 examples) and high chemical yield (up to 99%) rendered this strategy particularly appealing for expanding the library of dispiro-oxindoles [120].The incorporation of 2H-azirines as dipolarophiles in cycloaddition reactions involving isatin-derived azomethine ylides has been explored by Kanizsai and coworkers, which presents a fascinating opportunity to investigate the potential reactivity and versatility of these compounds.They elaborated a regio-and diastereoselective 1,3dipolar cycloaddition of 2H-azirines with azomethine ylides generated in situ from isatins

Dipolarophiles Containing Unsaturated C=N Double Bonds
In terms of dipolarophiles of 1,3-dipolar cycloaddition, a considerable number of alkenes and alkynes have been subjected to 1,3-DC leading to the formation of various spiro-oxindolopyrrolidines and spiro-pyrrolines.On the other hand, the synthesis of analogous spiro-oxindoloimidazolidines using imines as dipolarophiles remains largely unexplored.Yang and co-workers developed a diversity-driven three-component 1,3-dipolar cycloaddition of isatins, amino acids, and isatin-derived ketimines 107 (Scheme 23).A variety of dispiro-oxindole-imidazolidine frameworks featuring adjacent quaternary carbon centers were facilely obtained in excellent yields under mild conditions (at room temperature).This protocol can be readily scaled up with simplified purification steps without compromising the chemical outcome.The broad substrate scope (34 examples) and high chemical yield (up to 99%) rendered this strategy particularly appealing for expanding the library of dispiro-oxindoles [120].

Dipolarophiles Containing Unsaturated C=N Double Bonds
In terms of dipolarophiles of 1,3-dipolar cycloaddition, a considerable number of alkenes and alkynes have been subjected to 1,3-DC leading to the formation of various spiro-oxindolopyrrolidines and spiro-pyrrolines.On the other hand, the synthesis of analogous spiro-oxindoloimidazolidines using imines as dipolarophiles remains largely unexplored.Yang and co-workers developed a diversity-driven three-component 1,3dipolar cycloaddition of isatins, amino acids, and isatin-derived ketimines 107 (Scheme 23).A variety of dispiro-oxindole-imidazolidine frameworks featuring adjacent quaternary carbon centers were facilely obtained in excellent yields under mild conditions (at room temperature).This protocol can be readily scaled up with simplified purification steps without compromising the chemical outcome.The broad substrate scope (34 examples) and high chemical yield (up to 99%) rendered this strategy particularly appealing for expanding the library of dispiro-oxindoles [120].Scheme 23.A diversity-driven three-component 1,3-dipolar cycloaddition of isatins, amino acids, and isatin-derived ketimines.
The incorporation of 2H-azirines as dipolarophiles in cycloaddition reactions involving isatin-derived azomethine ylides has been explored by Kanizsai and coworkers, which presents a fascinating opportunity to investigate the potential reactivity and versatility of these compounds.They elaborated a regio-and diastereoselective 1,3dipolar cycloaddition of 2H-azirines with azomethine ylides generated in situ from isatins and α-amino acids, affording an unprecedented aziridine-fused spiro[imidazolidine-4,3′- The incorporation of 2H-azirines as dipolarophiles in cycloaddition reactions involving isatin-derived azomethine ylides has been explored by Kanizsai and co-workers, which presents a fascinating opportunity to investigate the potential reactivity and versatility of these compounds.They elaborated a regio-and diastereoselective 1,3-dipolar cycloaddition of 2H-azirines with azomethine ylides generated in situ from isatins and α-amino acids, affording an unprecedented aziridine-fused spiro[imidazolidine-4,3 -oxindole] framework (Scheme 24).This one-pot three-component reaction exhibits broad substrate tolerance (33 examples) and enables facile construction of highly diverse 1,3-diazaspiro[bicyclo[3.1.0]hexane]oxindoles under mild conditions with isolated yields up to 81%.Mechanistically, the reaction between azomethine ylides and 2H-azirine can proceed via both endo-transition state (TS) and exo-transition state (TS); no evidence was discovered regarding the formation of exocyclic products.The exclusive formation of endo-cycloadducts 102a and 102b may be attributed to steric repulsion between the methyl substituent of the azirine moiety and the phenyl substituent of oxindole in exo-TS.Due to its more favorable S-shaped conformation over U-shaped conformation, endo-selective 1,3-DC leads to the predominant formation of diastereomer 102a [121].
Molecules 2023, 28, x FOR PEER REVIEW 19 of 26 diazaspiro[bicyclo[3.1.0]hexane]oxindolesunder mild conditions with isolated yields up to 81%.Mechanistically, the reaction between azomethine ylides and 2H-azirine can proceed via both endo-transition state (TS) and exo-transition state (TS); no evidence was discovered regarding the formation of exocyclic products.The exclusive formation of endo-cycloadducts 102a and 102b may be attributed to steric repulsion between the methyl substituent of the azirine moiety and the phenyl substituent of oxindole in exo-TS.Due to its more favorable S-shaped conformation over U-shaped conformation, endoselective 1,3-DC leads to the predominant formation of diastereomer 102a [121].

Other Dipolarophiles
The versatility of 2-indolylmethanols as reactants in the synthesis of indole derivatives or indole-fused cyclic frameworks has been well-documented [122][123][124][125].However, there is a limited number of examples showcasing catalytic enantioselective cycloadditions utilizing 2-indolylmethanols as nitrogen-carbon-carbon (NCC) or three carbon (3C) building blocks.The chiral phosphoric acid-catalyzed enantioselective and regioselective [3 + 3] cycloaddition of isatin-derived azomethine ylides was conducted in 2017, employing C3-unsubstituted 2-indolylmethanols as NCC building blocks (Scheme 25).This reaction afforded chiral spiro-oxindoles with significant yields, displaying moderate to good enantioselectivities and excellent diastereoselectivities (up to 85% yield, 96:4 er, all > 95:5 dr) [126].Chiral unnatural amino acids (AAs) are highly sought after in the fields of biochemistry and pharmaceuticals due to their extensive applications for peptide and protein modification, enhancement of metabolic stability, reduction in aggregation, improvement of pharmacokinetic properties, and facilitation of blockbuster drug design [127][128][129][130].The Ni(II) complex is a widely recognized and versatile tool for the synthesis of challenging enantiopure amino acids.Notably, the chiral auxiliary released after isolation of the amino acid can be conveniently recovered through precipitation and reused in the synthesis of the initial Ni(II) complex.In 2022, Larionov and co-workers reported a protocol for the asymmetric synthesis of artificial amino acids featuring a 3spiropyrrolidine oxindole skeletal with continuous tetra-substituted carbon stereocenters (Scheme 26).This was achieved through a 1,3-dipolar cycloaddition reaction of in-situgenerated azomethine ylides with a chiral dehydroalanine Ni(II) complex 109.The quantum chemical calculation was employed to elucidate the formation of distinct regioisomers in sarcosine and proline.The acidic decomposition of Ni(II) complexes 110 afforded the desired unnatural complex AAs 111 featuring a 3-spiropyrrolidine oxindole core.The chiral auxiliary ligand was reclaimed and employed for the synthesis of the initial dehydroalanine complex-substrate [131].Scheme 26.An asymmetric 1,3-dipolar addition of azomethine ylides to a chiral dehydroalanine Ni(II) complex.

Conclusions
The one-pot 1,3-dipolar cycloaddition reactions have emerged as a prominent research area in the field of multicomponent reactions, garnering significant attention from both organic and medical chemistry communities.Multicomponent one-pot 1,3dipolar cycloaddition reactions offer a versatile approach for synthesizing natural products, heterocyclic scaffolds, medicinal drug molecules, and functional materials.Chiral unnatural amino acids (AAs) are highly sought after in the fields of biochemistry and pharmaceuticals due to their extensive applications for peptide and protein modification, enhancement of metabolic stability, reduction in aggregation, improvement of pharmacokinetic properties, and facilitation of blockbuster drug design [127][128][129][130].The Ni(II) complex is a widely recognized and versatile tool for the synthesis of challenging enantiopure amino acids.Notably, the chiral auxiliary released after isolation of the amino acid can be conveniently recovered through precipitation and reused in the synthesis of the initial Ni(II) complex.In 2022, Larionov and co-workers reported a protocol for the asymmetric synthesis of artificial amino acids featuring a 3-spiropyrrolidine oxindole skeletal with continuous tetra-substituted carbon stereocenters (Scheme 26).This was achieved through a 1,3-dipolar cycloaddition reaction of in-situ-generated azomethine ylides with a chiral dehydroalanine Ni(II) complex 109.The quantum chemical calculation was employed to elucidate the formation of distinct regioisomers in sarcosine and proline.The acidic decomposition of Ni(II) complexes 110 afforded the desired unnatural complex AAs 111 featuring a 3-spiropyrrolidine oxindole core.The chiral auxiliary ligand was reclaimed and employed for the synthesis of the initial dehydroalanine complex-substrate [131].Chiral unnatural amino acids (AAs) are highly sought after in the fields of biochemistry and pharmaceuticals due to their extensive applications for peptide and protein modification, enhancement of metabolic stability, reduction in aggregation, improvement of pharmacokinetic properties, and facilitation of blockbuster drug design [127][128][129][130].The Ni(II) complex is a widely recognized and versatile tool for the synthesis of challenging enantiopure amino acids.Notably, the chiral auxiliary released after isolation of the amino acid can be conveniently recovered through precipitation and reused in the synthesis of the initial Ni(II) complex.In 2022, Larionov and co-workers reported a protocol for the asymmetric synthesis of artificial amino acids featuring a 3spiropyrrolidine oxindole skeletal with continuous tetra-substituted carbon stereocenters (Scheme 26).This was achieved through a 1,3-dipolar cycloaddition reaction of in-situgenerated azomethine ylides with a chiral dehydroalanine Ni(II) complex 109.The quantum chemical calculation was employed to elucidate the formation of distinct regioisomers in sarcosine and proline.The acidic decomposition of Ni(II) complexes 110 afforded the desired unnatural complex AAs 111 featuring a 3-spiropyrrolidine oxindole core.The chiral auxiliary ligand was reclaimed and employed for the synthesis of the initial dehydroalanine complex-substrate [131].Scheme 26.An asymmetric 1,3-dipolar addition of azomethine ylides to a chiral dehydroalanine Ni(II) complex.

Conclusions
The one-pot 1,3-dipolar cycloaddition reactions have emerged as a prominent research area in the field of multicomponent reactions, garnering significant attention from both organic and medical chemistry communities.Multicomponent one-pot 1,3dipolar cycloaddition reactions offer a versatile approach for synthesizing natural products, heterocyclic scaffolds, medicinal drug molecules, and functional materials.

Conclusions
The one-pot 1,3-dipolar cycloaddition reactions have emerged as a prominent research area in the field of multicomponent reactions, garnering significant attention from both organic and medical chemistry communities.Multicomponent one-pot 1,3-dipolar cycloaddition reactions offer a versatile approach for synthesizing natural products, heterocyclic scaffolds, medicinal drug molecules, and functional materials.Among them, the in situ generation of azomethine ylides from isatins and amino acids with dipolarophiles represents the most fascinating strategy.The abundance and easy availability of starting materials enable the construction of a diverse library of spiro-oxindole scaffolds.In addition to azomethine ylides, a wide range of dipolarophiles including unsaturated C=C bonds with electron-withdrawing groups such as cyano, tosyl, ketone, ester, carboxylic acid, nitro, and amide can be effectively utilized in diversity-oriented reactions.However, it is worth noting that there continues to be a scarcity of more intricate dipolarophiles, and experts may propose innovative alternative components for constructing structures with potential medical applications.On the other hand, devising effective strategies for asymmetric catalytic synthesis and the manipulation of product core skeletons remains an immensely desirable yet formidable task.

Figure 1 .
Figure 1.Representative natural products and bioactive compounds with the spiropyrrolidine oxindole scaffolds.

Scheme 7 . 7 .
Scheme 7. Synthesis of a series of spiro-oxindole pyrrolidine-grafted thiochromene scaffolds as potential anticancer agents.In 2021, Zhu et al. accomplished the synthesis of a library of functionalized coumarin ring-grafted spiro or dispiro-oxindole heterocycles via a simple and efficient one-pot three-component 1,3-dipolar cycloaddition reaction involving diverse dipolarophiles and Scheme 7. Synthesis of a series of spiro-oxindole pyrrolidine-grafted thiochromene scaffolds as potential anticancer agents.